Despite the structural, and biochemical changes reported to occur in aging brain, the mechanism(s) underlying the aging process itself remain unknown. Thus, we have begun a new project designed to explore differential gene expression in old and young rat brain. Using subtraction hybridization techniques we are attempting to clone genes which are differentially expressed in aged (24 month) and mature young (5 month) rats. Briefly, the basic approach is to construct two cDNA libraries; one from poly A+ RNA from young rats, the other from poly A+ RNA from old rats. Poly A+ RNA from one age group is hybridized to the cDNA derived from the opposite age group and the cDNA/mRNA hybrids removed. AS a result, nonhybridizing cDNAs obtained and subsequently package in a bacterial vector, should be enriched or highly specific for a particular age group. Ultimately, this will give us the opportunity to identify and study those genes which are involved (associated) with the aging process in brain by virtue of their increased expression (or conversely, by their relative inactivity) at specific ages.